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Title:

Pharmaceutical formulations for dry powder inhalers

Abstract:

A powder for use in a dry powder inhaler comprises: i) a fraction of fine particle size constituted by a mixture of physiologically acceptable excipient and an additive; ii) a fraction of coarse particles; and iii) at least one active ingredient. The powder is suitable for efficacious delivery of active ingredients into the low respiratory tract of patients suffering from pulmonary diseases such as asthma. In particular, the invention provides a formulation to be administered as dry powder for inhalation which is freely flowable, can be produced in a simple way, is physically and chemically stable and capable of delivering accurate doses and/or high fine particle fraction of low strength active ingredients by using a high- or medium resistance device.

1. A powder for use in a dry powder inhaler, the powder comprising: i) a fraction of fine particle size comprising composite particles prepared by co-micronising a physiologically acceptable excipient and a surface active additive, the fraction having a mean particle size of less than 35 .mu.m; ii) a fraction of coarse particles constituted of a physiologically acceptable carrier having a particle size of at least 90 .mu.m; and iii) at least one active ingredient having a particle size of less than 10 .mu.m; said fine fraction (i) being composed of up to 99% by weight of particles of the excipient and at least 1% by weight of additive and the ratio between the fine excipient particles and the coarse carrier particles being between 1:99 and 40:60% by weight, and wherein the additive partially coats the surfaces of both the excipient and the coarse particles, and wherein the active ingredients are not selected from the group consisting of budesonide, and its epimers, formoterol, TA2005 and its stereoisomers, salts thereof, and combinations thereof.

2. A powder according to claim 1, which is in the form of `hard pellets`.

3. A powder according to claim 1, wherein the mixture (i) is composed of from 90 to 99% by weight of the excipient particles and from 1 to 10% by weight additive.

4. A powder according to claim 1, wherein the ratio between the fraction with a fine particle size and the coarse particle fraction is at least 10:90.

5. A powder according to claim 4, wherein the ratio between the fraction with a fine particle size and the coarse particle fraction is comprised between 15:85 and 30:70% by weight.

6. A powder according to claim 1, wherein the coarse particle fraction is constituted of a physiologically acceptable excipient which has a particle size of 100 to 400 .mu.m.

7. A powder according to claim 1, in which the particle size of the mixture (i) is less than 15 .mu.m.

8. A powder according to claim 1, in which the fraction with a fine particle size is composed of 98% by weight of the physiologically acceptable excipient and 2% by weight of the additive and the ratio between the fraction with a fine particle size and the coarse particle fraction is 10:90% by weight.

9. A powder according to claim 1, in which the coarse carrier particles have a tapped density not exceeding 0.7 g/cm.sup.3.

10. A powder according to claim 1, in which the coarse carrier particles have a bulk density as measured by mercury porosimetry of not exceeding 0.6 g/cm.sup.3.

11. A powder according to claim 1, wherein the additive is selected from the classes of lubricants, anti-adherents or glidants.

12. A powder according to claim 1, wherein the additive is magnesium stearate.

13. A powder according to claim 1, wherein the physiological acceptable excipient is one or more crystalline sugars.

14. A powder according to claim 1, wherein the physiological acceptable excipient is a-lactose monohydrate.

15. A powder according to claim 1, wherein the active ingredient has a particle size less than 6 .mu.m.

16. A powder according to claim 1, comprising more than 5% by weight, based on the total weight of the formulation, of particles of aerodynamic diameter less than 20 .mu.m, the formulation having a flowability index of 12 mm or less.

17. A powder according to claim 16, comprising more than 10% by weight, based on the total weight of the formulation, of particles of aerodynamic diameter less than 20 .mu.m, the formulation having a flowability index of 12 mm or less.

18. A process for making a powder according to claim 1, said process including the steps of: (a) co-micronising the excipient particles and the additive particles so as to significantly reduce their particle size and produce composite particles; (b) spheronising by mixing the resulting composite particles with the coarse carrier particles such that mixture particles adhere to the surface of the coarse carrier particle; (c) adding by mixing the active particles to the spheronised particles.

19. A process according to claim 18, wherein step a) is carried out by milling.

20. A process according to claim 19, wherein step a) is carried out using a jet mill.

21. A process for making a powder according to claim 1, said process including the steps of: (a) mixing in a Turbula or high-energy mixer the excipient particles and the additive particles wherein the excipient particles have a starting particle size less than 35 .mu.m; (b) spheronising by mixing the composite particles with the coarse carrier particles such that composite particles adhere to the surface of the coarse carrier particles; (c) adding by mixing the active particles to the spheronised particles.

22. A process according to claim 21, wherein the excipient particles of step a) have a starting particle size of less than 15 .mu.m.

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